Preparation of 7 - chloro-2 2-dihydro-1-methyl-5-phenyl - 1h -1 4-benzodiazepine from 2 3 -dihydro-1-methyl-5-phenyl-1h-1 4-benzodiazepine by chlorination

ABSTRACT

7 - CHLORO-2,3-DIHYDRO-1-METHYL-5-PHENYL-1H-1,4-BENZODIAZEPINE (A) FROM 2,3-DIHYDRO-1-METHYL-5-PHENYL-1H-1,4BENZODIAZEPINE BY CHLORINATION. (A) IS USEFUL AS AN ANTICONVULSANT, MUSCLE RELAXANT AND SEDATIVE AGENT.

United States Patent US. Cl. 260-239 7 Claims ABSTRACT OF THE DISCLOSURE 7 chloro-2,3-dihydro-l-methyl-S-phenyl-lH-1,4-benzodiazepine (A) from 2,3-dihydro-l-methyl-S-phenyl-1H-1,4- benzodiazepine by chlorination. (A) is useful as an anticonvulsant, muscle relaxant and sedative agent.

The present invention relates to the preparation of a compound of the formula halo wherein R is lower alkyl from the corresponding compounds of the formula i /NCH3 wherein R is as above by halogenating the latter with a halogenating agent. Preferably, the halogen group in position-7 of compounds of the Formula I above is chlorine.

Compounds of the Formula I are known prior to the present invention as being pharmaceutical agents by virtue of their pharmacological activity.

The process which constitutes the present invention comprises reacting a compound of the Formula II above with a halogenating agent selected from the group consisting of halogen, a lower alkyl hypohalite and a halogenating agent containing a group wherein X is halogen, preferably selected from the group consisting of bromine and chlorine, most preferably chlorine.

When a halogen is utilized as the halogenating agent, preferred is the halogen chlorine.

When a lower alkyl hypohalite is utilized as the halogenating agent, preferred are lower alkyl hypochlorites such as tertiary butyl hypochlorite.

Patented Jan. 18, 1972 Ice Preferred among the many halogenating agents which contain a a compound of the formula III-a and a compound of the formula Y III-o wherein X is as above, I connotes unsubstitution or substitution and Y is selected from the group consisting of hydrogen and lower alkyl.

When I connotes substitution, preferably, it is indicative of a lower alkyl group. That is to say, that a lower alkyl group is positioned on the phenyl nucleus of the the compound of the Formula III-c above.

Illustrative of compounds Within the genus encompassed by Formula III-a above, III-b above and III-c above are N-chlorosuccinimide, N-bromosuccinimide, N-halo-lower alkanoyl amides, e.g. N-chloroacetamide, N-chlorosulfonamides, such as chloroamine-B, chloroamine-T and the like.

When a compound containing the group is utilized, a free radical catalyst may also be present in the reaction medium, although the presence of a free radical catalyst is not essential to a successful performance of the process aspect described herein. Any suitable free radical catalyst which possesses the capability of promoting halogenating in position-7 of the compounds of the Formula II above is included within the purview of the present invention. Illustrative of suitable catalysts are azo-bi slower alkyl nitriles, such as aZobis-isobutyronitrile and 2,2-azobis-(Z-methylpropionitrile), di-lower alkyl peroxides, such as di-t-butyl peroxides, di-acyl peroxides such a di-lower alkanoyl peroxides (e.g. acetyl peroxide), peresters :such as t-butyl perbenzoate and t-butyl perphthalate, hydroperoxides such as t-butyl hydroperoxide and cumene hydroperoxide and the like. Preferred among the many free radical catalysts utilizable in the process aspects of the present invention are azo-bis-lower alkyl nitriles. A preferred combination of halogenating agent and free radical catalyst consists of a mixture containing N-chlorosuccinimide and 2,2'-azobis(Z-methylpropionitrile).

In an advantageous aspect of the present invention, the conversion of a compound of the Formula II into the corresponding compound of the Formula I is effected utilizing an inert organic solvent as the reaction medium. Suitable solvent media are represented by a weak organic acid such as a lower alkanoic acid, e.g. acetic acid, formic acid and the like, a chlorinated hydrocarbon, such as chlorobenzene, carbon tetrachloride, methylene dichloride, chloroform and the like. When a lower alkanoic acid 3 is utilized as the reaction medium, the reaction medium can be buffered by adding thereto a buffer such as potassium acetate, potassium carbonate, triethylamine and the like.

The term lower alkyl as utilized throughout the present specification is intended to connote C C, branched and straight chain hydrocarbon radicals, such as methyl, ethyl, isopropyl, butyl and the like. In the most advan- Suitably, when a halogen atom is utilized as the halo- 5 tageous process aspect of the present invention, a comgenating agent, the preferred solvent medium is a lower pound of the Formula I wherein R is a methyl group are alkanoic acid. prepared.

When a lower alkyl hypohalite is utilized as the halo- Thus, the present invention relates to a novel and genating agent, the preferred solvent medium is a chlounique process of effecting the conversion of a compound rinated hydrocarbon. Furthermore, when a halogenating bearing unsubstitution on the fused portion of a benzoagent containing the group diazepine nucleus into the corresponding compound I which contains halogen thereat. In the most advantageous NX process aspect of the present invention, the halogenation is utilized as the reagent which provides the halogen eflected Wlth an atom, a chlorinated hydrocarbon is most suitably em- 15 ployed as the medium in which the conversion of a compound of the Formula II into the corresponding comcontaining halogenating agent, preferably, N-chlorosucpound of the FormulaIis effected. cinimide. By utilizing N-chlorosuccinimide there is ob- Temperature and pressure are not critical features of tained the highest yields of the compound of the Formula the above reaction. Thus, the reaction can be effected at I from the corresponding compound of the Formula II room temperature and atmospheric pressure or above above. room temperature. It should be apparent to those skilled The following examples are illustrative but not limitain the art that the temperature at which the conversion tive of the present invention. All temperatures specified of the compound of the Formula II above into h GOP in the disclosure in the sepcification are in degrees centiresponding compound of the Formula I above is effected de, is determined in part by the halogenating agent utilized. EXAMPLE 1 For example, if the reaction is conducted utilizing halogen, it is preferred to conduct the reaction at a tempera- A solutlon of 100 (0423 l of Y ture range of about 10 to about 40, most preferably l'methyl'sphenyl'lH P P and at room temperature. (0.45 mrnole) of N-chlorosuccinimide in 3 ml. of methylwhen the Iowa. alkyl hypochlorite or the agent ene chloride was heated to a gentle reflux under nitrogen mining the for 21 hr. Solvent was evaporated in vacuo. The residue was triturated five times with 5 ml. portions of eflier. The L combined ether extracts were filtered through a plug of grouping is utilized as the halogen providing agent, it is Cotton then washed three i f pOr.nOnS of water to remove last traces of succinimide. Drying over preferred to perform the reaction at elevated temperaanhydrous sodium sulfate followed by evaporation of tures, e.g. at about the reflux temperature of the reaction a ether gave a yellow gum, which was flask distilled at 200 medium in which the process is being conducted. Further- (0.02 mm.). The resulting medium was separated on a more, should a free radical catalyst be present, it should 40 20 cm. x 20 cm. x 2 mm. silica gel plate using ethyl acebe equally readily apparent to those skilled in the art that tate as eluent. The yellow band was scraped off the plate the temperature at which the conversion of a compound and eluted with 5 percent methanol in ethyl acetate. The of Formula II above into the corresponding compound eluent was evaporated off and the oil which was obtained of the Formula I above is effected 1S determined in part I thusly was replated on two more of the same plates. by the free radical catalyst employed. It is well known a 4;, Elution this time gave a crystalline material which after that some radical formation which is caused by bond recrystallizations from hexane gave 7-chloro-2,3-dihydrodissociation occurs at room temperature. Thus, with a Lmeth hen 44361120 diaze mg as faintly free radical catalyst which dissociates at room tempera- 10W riyms 9-9 1 P y ture, the reaction may be conducted at such a temperature. p s

Most free radical catalysts, however, dissociate at above r0 EXAMPLE 2 room temperature. Thus, in the more preferred process 0 aspect, should a free radical catalyst be present, it is 7 -chlo ro-2,3-dihydro-l-methyl-S-phenyl-1H 1,4 benpreferential to conduct the reaction at elevated temperazodiazepine was prepared from 2, 3-dihydro-l-methyl-5- tures, again advantageously at about the reflux temperaphenyl-1H1,4-benzodiaziep1ne utilizing the following mature of the reaction medium. terials and reaction conditions:

Conditions F Mole fS'Siiil Mole ra i eal Weight Ternpcr- Time, Method of Example Chlorinatiiig agent equiv. Solvent strate, M Bufier equiv. catalyst percent ature hrs. analysis 1.2 HOA 0.5 KOA 22 TLC. 2.6 A: 0 2 c 16 VPC. 4 1.2 HCOzH 60 VPC. 5 1.2 ooh 160 TLC. 6 .do... 1.5 CHCli VPC. 7 t-Butyl hypochlorite 1.5 CCli 16 VPC. 8 N-chloro succiuimide 1.1 0014 16 Prepaatlve NMR 5 1.1 C014 16 VPC. 1.1 0H201: 2i VPG 1.1 CHQCIZ 21 vPc 2.1 0112012 16 VPC 2.0 0014 16 'ILC. 6.0 CHzGh 2O VPC' Free radical catalyst=2,2'-azobis(2-metliylpropionitrile).

2 TLC=tliin layer chromatography, VPC=vapor phase chromatography. NMR=riuclear magnetic resonance spectroscopy.

3 Freshly standardized (iodide-thiosultate) before each use. 4 Solid suspension.

l Small sample collected by preparative VlC and identified by mixture M.P.

ltleiitified by infrared and mixture M.P.

We claim: 1. A process for the preparation of a compound of the formula N-CH CH2 ChlOl'O wherein R is lower alkyl from the corresponding compound of the formula N-CHZ CH2 \C=N wherein R is as above by chlorinating in the presence of an inert organic solvent, the compound of the Formula II above with a chlorinating agent selected from the group consisting of chlorine, a lower alkyl hypochlorite and a chlorinating agent containing a lr x group selected from the group consisting of a compound of the formula a compound of the formula H l lower alkylCN-X and a compound of the formula wherein X is chloro, I connotes unsubstitution or substitution with lower alkyl and Y is selected from the group consisting of hydrogen and lower alkyl.

2. A process as defined in claim 1 wherein R is methyl.

3. A process as defined in claim 1 wherein the chlori nating agent is selected from the group consisting of chlorine, a lower alkyl hypochlorite and N-chlorosuccinimide.

4. A process as in claim 3 wherein R is methyl.

5. A process as defined in claim 2 wherein the chlorinating agent utilized is N-chlorosuccinimide.

6. A process as defined in claim 5 wherein a free radical catalyst is present.

7. A process as defined in claim 6 wherein the free rad ical catalyst utilized is 2,2-azobis(Z-methylpropionitrile).

References Cited UNITED STATES PATENTS 2/ 1964 Keller et a1 260239 OTHER REFERENCES ALEX MAZEL, Primary Examiner I. A. NARCAVAGE, Assistant Examiner US. Cl. X.R. 

